Alterations in left ventricular (LV) structure and function have been reported among the cardiac manifestations of systemic lupus erythematosus (SLE),1–6 including echocardiographic evidence of increases in LV wall thicknesses and mass, a decrease in LV ejection fraction, and impaired diastolic filling. However, the extent to which these findings might be due to renal disease or other concomitant cardiovascular disease, including hypertension, valvular heart disease, or coronary artery disease, has not been fully elucidated. Thus, it is currently uncertain whether abnormalities of LV structure and function in SLE are disease-related effects or are a result of other predisposing conditions.

Mechanisms by which SLE might directly induce changes in LV structure include underlying inflammatory processes leading to subclinical vasculitis, myocarditis, or vascular stiffening. Since the advent of corticosteroid therapy, vasculitis and myocarditis are rare findings in SLE patients who undergo autopsy.7–9 In contrast, we recently documented marked increases in arterial stiffness in SLE patients compared with control subjects, a finding that was directly related to chronicity of disease and circulating markers of inflammation.10 Ventricular remodeling and subsequent hypertrophy may therefore result from increased inflammation-mediated vascular stiffness. In addition, preclinical coronary artery disease also may be a contributing factor to LV structural changes, given the premature development of atherosclerosis in SLE patients.11,12

Clinical Perspective p 426

In the present study, we compared SLE patients with a reference group to evaluate the prevalence of LV hypertrophy in SLE patients and to determine whether this was a consequence of traditional stimuli or related to aspects of the disease (serological markers, inflammatory mediators, treatment, premature atherosclerosis). To eliminate confounding aspects of earlier studies, we specifically excluded SLE patients with renal failure and clinical or echocardiographic evidence of significant valvular or coronary heart disease. We hypothesized that LV hypertrophy would be more prevalent and that such hypertrophy could result from increased vascular stiffness or from premature generalized atherosclerosis.

Methods

Study Design

A total of 203 patients with SLE were consecutively recruited from the Autoimmune Disease Registry at the Hospital for Special Surgery at the time of outpatient visits. All patients met the diagnostic criteria of the American College of Rheumatology.13 Exclusion criteria included pregnancy, renal failure (serum creatinine ≥3.0 mg/dL and/or creatinine clearance ≤30 mL/min), evidence of clinical coronary artery disease, and echocardiographic evidence of segmental wall motion abnormalities or greater than mild aortic or mitral valve disease. Fifteen patients were excluded on the basis of significant valvular disease alone (10 patients had mitral regurgitation, 4 had aortic regurgitation, and 1 had both). Clinical coronary artery disease was found in 8 patients, 2 with myocardial infarction (documented by segmental wall motion abnormalities) and 6 with angina (confirmed by abnormal coronary angiography in 5 and abnormal perfusion scan in 1). Two of the patients with coronary artery disease also had overlapping valvular disease. Patients were matched to referent subjects on the basis of age (within 5 years) and gender. Referent subjects were drawn from normotensive and hypertensive subjects participating in National Institutes of Health–funded studies using similar imaging protocols and performed at Cornell University.14,15 None of the referent subjects had clinical coronary artery disease or significant valvular disease. A total of 6 patients could not be matched to suitable referent subjects. Finally, 1 patient was excluded because of a lack of LV mass data on echocardiography.

Cardiovascular risk factors, including serum lipids, smoking history, body mass index, and the presence or absence of diabetes mellitus and hypertension (defined by a blood pressure of at least 140/90 mm Hg or the use of antihypertensive medications), were assessed in all subjects. Antihypertensive medications were systematically withdrawn at least 3 weeks before study in the hypertensive referent subjects but not in hypertensive SLE patients (38 SLE patients were taking antihypertensive medications at the time of study). Comprehensive medical histories of SLE patients were obtained via interview and chart review using a standardized data collection instrument. Disease activity and disease-related damage were assessed with the use of the Systemic Lupus Erythematosus Disease Activity Index16 and the Systemic Lupus International Collaborating Clinics Damage Index,17 respectively. Medication records were obtained that included use of prednisone, azathioprine, cyclophosphamide, and methotrexate. Serological markers of SLE, including inflammatory mediators and specific antibodies, were obtained using standardized laboratory assays. The study protocol was reviewed by the institutional review board, and all participants gave written informed consent.

Ultrasonographic Studies

Echocardiography was performed by an experienced research technician using standard techniques and interpreted by a single cardiologist who was unaware of the clinical characteristics of the patients and referent subjects. Measurements of LV dimensions and reference limits for LV mass were made according to American Society of Echocardiography recommendations.18 LV mass (LVM) was calculated using the following formula: LVM=0.8 {1.04[(LVIDd+PWTd+SWTd)3−(LVIDd)3]}+0.6 g, where LVID is LV internal dimension, PWT is posterior wall thickness, SWT is septal wall thickness, and subscript d represents end diastole. LV mass was indexed for either body surface area or the power of its allometric or growth relation with height (height2.7). This latter method of indexation of LV mass allows better detection of hypertrophy that is related to obesity and improves prediction of cardiovascular risk.19,20 LV hypertrophy was considered present if the mass index exceeded 45 g/m2.7 in women or 49 g/m2.7 in men. Hypertrophy was termed eccentric or concentric on the basis of the presence of normal (<0.43) or increased (≥0.43) relative wall thickness (2×PWTd/LVIDd), respectively. LV systolic function was evaluated by ejection fraction with the Teichholz correction21 and fractional shortening. Stroke volume was calculated by multiplying the time velocity integral of flow at the aortic annulus by its cross-sectional area.

Carotid atherosclerosis was evaluated with ultrasonography of the right and left common, internal, and external carotid arteries using a standardized protocol.12,22 Multiple projections were used to identify the presence of atherosclerosis (plaque), which was defined as a focal protrusion >50% beyond the thickness of the surrounding wall. The end-diastolic intimal-medial thickness and minimum and maximum diameters of the common carotid arteries were measured from 2-dimensionally guided M-mode images during several cycles, and the values were averaged.

Measurement of Arterial Stiffness

Patients with SLE underwent assessment of arterial stiffness from pressure-diameter relations of the common carotid artery and pressure waveforms obtained by applanation tonometry of the radial artery. A high-fidelity transducer was used with adjustment of orientation and pressure to achieve optimal applanation of the artery. Central arterial waveforms and pressures were calculated with the SphygmoCor device using a generalized transfer function (AtCor Medical, Sydney, Australia) and calibrated using the brachial mean and diastolic pressures. Applanation tonometry has been shown to yield accurate estimates of intra-arterial pulse pressure.23–25 Minimum (end-diastolic) and maximum (peak systolic) diameters were obtained from carotid ultrasonography performed immediately before applanation tonometry with the position of the subject and ambient environment unchanged. Arterial stiffness was estimated with the arterial stiffness index (β): ln(Ps/Pd)/([Ds−Dd/Dd]), where Ps and Pd are aortic systolic and diastolic pressures, respectively, and Ds and Dd are carotid systolic and diastolic diameters, respectively. The arterial stiffness index has been shown to be a relatively pressure-independent measure of arterial stiffness.26

Laboratory Assessment

Patients with SLE underwent laboratory testing, including measurement of routine chemical analysis, including serum creatinine, total cholesterol and lipoprotein (a), measurement of serum complement C3 and C4, high-sensitivity C-reactive protein, and antibody testing, including double-stranded DNA, Smith, ribonuclear protein, Ro, La, and antiphospholipid antibodies (positive if level of either anticardiolipin IgG or IgM exceeded 40 isotype phospholipid units per milliliter or if lupus anticoagulant was present27). Serum interleukin-6 and tumor necrosis factor p55 and p75 receptors were measured with the use of kits (BioSource International, Carlsbad, Calif). Soluble intracellular adhesion molecule-1 and vascular adhesion molecule-1 were measured with an ELISA. Fasting homocysteine levels were obtained before and after the oral administration of methionine.28 CD40 ligand was measured as previously described.29

Statistical Analyses

Comparisons between SLE patients and referent subjects and between patients with and those without LV hypertrophy were made by using 2-sample t tests for continuous variables and by χ2 analysis for categorical variables. Results of continuous variables are presented as mean±SD unless otherwise stated. Comparisons between groups subdivided according to blood pressure and disease status were performed using ANOVA with post hoc testing for multiple comparisons. Bivariate relationships with LV mass were assessed using the Pearson correlation coefficient. All variables that had significant bivariate relations (as defined by P<0.05) with the outcome were evaluated for inclusion in a model predicting LV mass using multivariable regression analysis; unstandardized regression coefficients (B) with their 95% confidence intervals are reported. Two-sided values of P<0.05 were considered to indicate statistical significance.

The authors had full access to and take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

Results

Description of SLE Patients

Among the 173 SLE patients included in the present study, prevalences of SLE diagnostic criteria were as follows: malar rash (45%), discoid rash (8%), photosensitivity (33%), oral ulcers (24%), arthritis (91%), serositis (45%), renal disorder (34%), neurological disorder (15%), and hematological disorder (54%). In addition, anti-DNA antibodies were present in 43%, anti-Smith in 11%, anti–ribonuclear protein in 27%, anti-La in 5%, anti-Ro in 41%, and antiphospholipid antibodies in 19%. The median Systemic Lupus Erythematosus Disease Activity Index was 2.0 (range, 0 to 22) and ≤4.0 in 68% at the time of study. Current or former use of prednisone was present in 90% of patients, whereas other immunosuppressive therapy was less common (azathioprine in 33%, cyclophosphamide in 20%, and methotrexate in 10%). Hydroxychloroquine had been used by 76% of patients; warfarin had been used by 15%. Lipid-lowering therapy had been used by only 5% of patients at the time of study.

Comparison of SLE Patients and Referent Subjects

By design, SLE patients and the reference group were matched for age and gender and did not differ in other traditional risk factors (Table 1). Mean systolic and diastolic blood pressures were higher in referent subjects, likely as a result of systematic withdrawal of antihypertensive medications. Similar to earlier findings, carotid atherosclerosis was detected much more frequently in the SLE patients. Likewise, carotid intimal-medial thickness was smaller and end-diastolic diameter was greater in the SLE patients, with overall slightly greater arterial mass (cross-sectional area) in the reference group. LV wall thicknesses, chamber dimensions, and mass were higher in SLE patients than in the reference group (Table 2), resulting in significantly higher LV mass and a higher prevalence of LV hypertrophy (all P<0.001). LV hypertrophy was eccentric in 29 of 31 SLE patients (93.5%) with hypertrophy and 7 of 11 referent subjects (63.6%) with hypertrophy. In addition, ejection fraction and cardiac output were higher in SLE patients (all P<0. 01). Left atrial and aortic dimensions also were significantly larger in SLE patients.

To further explore the extent to which arterial stiffness is related to traditional risk factors as opposed to disease-related factors, we examined bivariate relations of arterial stiffness to the variables listed in Table 5, as well as to pharmacological therapy, autoantibodies, and the presence of carotid atherosclerosis. Individual correlates of stiffness included age (or age at diagnosis), mean arterial pressure, diabetes, presence of carotid atherosclerosis (all P<0.001), SLE duration (P=0.005), and the Systemic Lupus International Collaborating Clinics Damage Index (P=0.022). In multivariable analyses, predictors of arterial stiffness were age at diagnosis, disease duration, diabetes (all P<0.001), and carotid atherosclerosis (P=0.023), whereas mean arterial pressure (P=0.079) and the damage index (P=0.16) were of borderline significance.

Relative Impacts of Hypertension and SLE on LV Hypertrophy

To understand better the extent to which SLE might augment the impact of hypertension, a potent stimulus to LV hypertrophy, the patient and reference groups were subdivided according to hypertension status. Among normotensive subjects, LV mass was strikingly increased in SLE patients compared with referent subjects independently of the method of expression (absolute LV mass, 134.7±28.5 versus 118.4±26.7 g; LV mass/body surface area, 77.4±12.9 versus 68.8±12.7 g/m2; LV mass/height2.7, 35.8±7.5 versus 31.4±6.5 g/ht2.7; all P<0.001). Similar findings were obtained in the hypertensive subset (absolute LV mass, 170.6±62.0 versus 118.4±26.7 g, P=0.049; LV mass/body surface area, 95.3±35.7 versus 81.5±15.7 g/m2, P=0.037; LV mass/height2.7, 45.6±17.0 versus 38.4±9.1 g/height2.7, P=0.017) in patients with and without SLE, respectively. LV mass index was lower in normotensive referent subjects than in the 3 other subgroups (P<0.005 for all). LV mass was increased in normotensive SLE patients to an extent comparable to that of hypertensive referent subjects. Furthermore, the presence of both SLE and hypertension resulted in a significant increase in LV mass beyond the presence of hypertension alone (the Figure). Consequently, although normotensive SLE patients and hypertensive referent subjects had comparable LV mass index (P=0.53), LV mass index was significantly higher in hypertensive SLE patients than in hypertensive subjects in the reference group (P=0.006).

Comparison of LV mass (indexed to height2.7) in normotensive (NL) and hypertensive (HTN) referent subjects and SLE patients. See text for subgroup comparisons.

Discussion

The present study demonstrates a significantly increased prevalence of LV hypertrophy in SLE patients compared with referent subjects with, on average, higher arterial pressure. Moreover, increases in LV mass index not only were related to the traditional stimuli of age, obesity (BMI), hypertension, and diabetes but also were associated with the presence of SLE per se. Thus, SLE, in addition to traditional stimuli, augments LV mass, especially in the setting of hypertension. These findings suggest a direct disease-related effect of SLE on LV structure. Our finding of arterial stiffness as a strong determinant of LV mass in SLE patients supports the hypothesis that inflammation-mediated vascular stiffening plays a significant role in LV structural changes in SLE. In addition, in the absence of clinical or echocardiographic evidence of coronary or significant valvular heart disease, systolic function was found to be preserved in SLE patients.

Although prior smaller studies have reported LV hypertrophy in SLE patients, these findings were either observational or confounded by concomitant valvular, cardiovascular, or renal disease. Cervera et al3 and Omdal et al4 reported LV hypertrophy in only 6 of 70 and 3 of 35 SLE patients, respectively, prevalences more comparable to those seen in our reference group, of whom 20% were hypertensive. Leung et al6 found significantly more LV hypertrophy in 75 SLE subjects compared with 60 control subjects when investigating the association of antiphospholipid antibodies with cardiac abnormalities. However, in that study, 48 patients were reported to have renal disease, and a total of 25 patients had mitral and/or aortic valve disease. In a more detailed study by Crozier et al,1 greater LV wall thicknesses and mass and lower ejection fractions were found in 50 SLE patients compared with control subjects; however, patients with valvular disease and pericardial effusion were included, and 14% of SLE patients and no control subjects had hypertension. In contrast, Fujimoto et al,2 in a study that excluded SLE patients with diabetes or ischemic and valvular heart disease, noted an increase in fractional shortening among SLE subjects compared with control subjects, consistent with the findings in the present study. The significantly greater end-diastolic yet comparable end-systolic dimensions found in SLE patients in our study suggest that increases in LV systolic performance result from the Starling phenomenon. Although other smaller studies have suggested a relation between LV systolic dysfunction and the presence of antiphospholipid antibodies,6,30 we did not detect such an association in our much larger sample.31

In addition to disease status, our findings show that age, BMI, hypertension, and diabetes mellitus contribute significantly to LV mass index, all of which are well-documented stimuli to LV hypertrophy.32–34 Other studies have attributed LV hypertrophy in SLE to the additional presence of hypertension.35–38 Our study documents that hypertension is not the primary cause of LV hypertrophy in SLE on the basis of comparable prevalences of hypertension in the patient and reference groups and on subgroup analyses in normotensive and hypertensive subjects demonstrating that the presence of both SLE and hypertension leads to increases in LV mass beyond the presence of hypertension alone. These findings are even more striking in that the diagnosis of hypertension may be less robust in SLE patients (ie, blood pressure may be primarily or exclusively elevated during flares, and antihypertensive medications were not discontinued for study purposes in SLE patients, whereas they were discontinued for weeks to months in our hypertensive referent subjects).

The associations of duration of disease, damage index, and higher levels of soluble intracellular adhesion molecule-1 and tumor necrosis factor p55 receptor with LV mass index in univariate analyses suggest that the duration and severity of the inflammatory state contribute to LV hypertrophy in SLE. Inflammatory mediators affect leukocytes, myocytes, and matrix and thereby contribute to remodeling and hypertrophy of the heart. Although these factors were not significant in multivariable analyses, we have previously demonstrated a marked increase in arterial stiffness in a subset of the SLE patients included in the present study versus age-matched control subjects (3.36±0.13 versus 2.60±0.13; P<0.001) that was associated with disease duration and circulating levels of C-reactive protein and interleukin-6,10 suggesting that arterial stiffening might summate the duration and severity of inflammation. Of note, use of immunosuppressive therapy was not related to LV mass, raising the possibility that nonspecific blockade of inflammatory mediators may not reestablish the balance necessary to remodel and restore the physical properties of large conduit arteries. Although subclinical myocarditis resulting from inflammation has been suggested as a possible mechanism for the increased incidence of heart failure among rheumatoid arthritis patients,39 myocarditis is unlikely to be the cause of LV hypertrophy among SLE patients in our study because myocarditis in lupus patients is marked by signs and symptoms of heart failure and echocardiographic evidence of depressed ejection fraction and wall motion abnormalities.40,41 Although LV mass index was significantly higher among SLE patients when carotid atherosclerosis was present, raising the possibility that subclinical coronary artery atherosclerosis might be the cause of LV hypertrophy among SLE patients, the presence of carotid atherosclerosis was not a determinant of LV mass index in multivariable analyses.

Limitations of our study include the lack of systematic assessment of LV diastolic filling parameters. Although abnormalities of diastolic filling have been reported in several small studies,2,42–46 among 131 SLE patients in our study with data on transmitral flow, deceleration time was prolonged in only 17 and isovolumic relaxation time was prolonged in only 2. Although newer techniques such as tissue Doppler imaging and strain rate may provide more specific detection of abnormal diastolic properties, no data exist to suggest such abnormalities might cause, rather than be a result of, an increase in LV mass. Another limitation is the single determination of inflammatory markers, which may not be an accurate representation of inflammatory burden over time. Although most hypertensive SLE patients were studied while taking antihypertensive medication, we believe the lack of antihypertensive medications in the hypertensive referent subjects would favor greater LV mass in this group, the opposite of our findings. In addition, the higher LV mass in normotensive SLE patients, despite slightly lower blood pressure (105±14/68±8 mm Hg in SLE patients versus 110±12/69±8 mm Hg in normotensive referent subjects; P=0.006 for systolic pressure), strongly argues in favor of SLE rather than blood pressure as the cause of increased LV mass.

Conclusions

SLE patients have an increased prevalence of LV hypertrophy that is not exclusively a result of concomitant coronary artery or valvular heart disease, renal involvement, premature subclinical atherosclerosis, or other traditional stimuli, including hypertension. Our results suggest that inflammation-mediated arterial stiffening, a strong determinant of LV hypertrophy, is likely the underlying mechanism for LV hypertrophy in SLE. LV hypertrophy is known to lead to increased risk of stroke, coronary artery disease, congestive heart failure, and sudden cardiac death in varied populations47–50 and therefore is likely to be a prognostic indicator of cardiac morbidity and mortality in SLE patients. Our findings suggest that more aggressive and targeted therapy may be needed to control the inflammation-mediated effects on vascular stiffening that lead to LV hypertrophy.

Acknowledgments

Sources of Funding

This work was supported by National Institutes of Health grants AR 45591 (National Institute of Arthritis and Musculoskeletal and Skin Diseases), HL47540 (National Heart, Lung, and Blood Institute), and M10RR0047 (Public Health Service Research Grant for the General Clinical Research Center).

CLINICAL PERSPECTIVE

Patients with systemic lupus erythematosus (SLE) develop premature cardiovascular disease independently of traditional risk factors. In addition, abnormalities of left ventricular (LV) structure and function have been reported in SLE patients, although the impact of concomitant coronary, valvular, and renal disease has not been taken into account. In the present study, we compared 173 SLE patients free of clinical or echocardiographic evidence of coronary artery disease, valvular heart disease, or renal failure with a comparable number of subjects from a reference sample. The presence of SLE strongly predicted increased LV mass but not LV systolic dysfunction. Increased LV mass was associated with arterial stiffness. We have previously reported a marked increase in arterial stiffness in patients with chronic inflammatory disease that is related to markers of inflammation. Insofar as LV hypertrophy is a potent marker of excess cardiovascular morbidity and mortality in other samples, this observation in SLE patients may indicate a subset of patients at increased risk. In addition, antiinflammatory therapy to control disease and to reduce arterial stiffening may be of benefit in reducing LV hypertrophy and thereby clinical cardiovascular disease.